Diseases of the Pituitary GlandDiseases of the Pituitary Gland
Benjamin Glaser, M.D.Endocrinology and Metabolism Service
Hadassah-Hebrew University Medical Center
Pituitary DiseasePituitary Disease
• Goals of lectures:– At the conclusion of the lectures and seminars (sadnaot) on
the pituitary gland, the student should be able to:• Describe the gross anatomy of the pituitary gland, and discuss the
relevance of the gland's embryology and anatomy to the physiology and pathology of the pituitary.
• Describe the normal control of secretion of vasopressin (ADH).– Describe the normal control of secretion of anterior pituitary hormones.
• Discuss the symptoms, clinical signs, laboratory evaluation and treatment of:
» Diabetes insipidus» Acromegaly» Prolactinoma » Panhypopituitarism
Human Pituitary in Sagittal SectionHuman Pituitary in Sagittal Section
Pituitary
Optic Chiasm
AnteriorCommissure
Hypothalamus
Third Ventricle
Pineal Body
MamillaryBody
MedianEminence
Anterior ClinoidsPosterior Clinoids
Carotids
The normal gross appearance of the pituitary gland removed from the sella turcica is shown here. The larger portion, the anterior pituitary (adenohypophysis), is toward the top. The image at the left shows the superior aspect of the pituitary with the stalk coming from the hypothalamus entering it. The inferior aspect of the pituitary is shown at the right. The posterior pituitary (neurohypophysis) is the smaller portion at the bottom.
Normal Pituitary: Gross anatomyNormal Pituitary: Gross anatomy
StalkAnterior
Posterior
Embryogenesis of the Human PituitaryEmbryogenesis of the Human Pituitary
Hypothalamic releasing hormones
, ADH
Normal Pituitary: Coronal MRINormal Pituitary: Coronal MRI
Optic Chiasm
InfundibulumCavernousSinus
Pituitary
Sphenoid sinus
Third Ventricle
Normal Pituitary: Sagittal SectionNormal Pituitary: Sagittal Section
Optic Chiasm
Infundibulum
Pituitary
Sphenoid sinus
SupraSellar fossa
Human Pituitary in Coronal SectionHuman Pituitary in Coronal Section
Pituitary glandInternal carotid artery
IIIIVVI
V
Sphenoid Sinus
Cranial Nerves
Human Pituitary in Coronal SectionHuman Pituitary in Coronal Section
Diseases of the PituitaryDiseases of the Pituitary
• Structural disorders– Trauma - stalk section
– Surgery
– Tumor• Functional
– Hormone Producing
• Non-functional– May affect hormone
production
• Functional disorders– Increased or decreased section
of hormones• LH (Leutinizing Hormone)• FSH (Follicle Stimulating
Hormone• ACTH (Adrenocorticotrophic
Hormone)• TSH (Thyroid Stimulation
Hormone)• Growth Hormone• Prolactin
Pituitary Gland HormonesPituitary Gland Hormones
TSHThyroidGland
Adrenal Gland
ACTH
LHFSH
Testes/Ovaries
GH Prolactin
IGF-1
Vasopressin(Anti-diuretic Hormone)
Oxytocin
Vasopressin BiosynthesisVasopressin Biosynthesis
Transport and Maturation
SP AVP NP GP
Production
Gene expression Preprohormone
SP, signal peptide; AVP, arginine vasopressin; NP, neurophysin; GP, glycoprotein
Cell body in paraventriculaor Supraoptic nucleus
AVP
Mature Hormone
GlycosylationProteolysisAmidation
Storage and release in posterior pituitary
AVP NP GP
Packaging
Prohormone
Receptor-mediated effects of AVPReceptor-mediated effects of AVP
Receptor
Subtype Site of Action Activation Effects
V1a
- vascular smooth muscle cells- platelets- lymphocytes and monocytes- liver
vasoconstrictionplatelet aggregationcytokine releaseglycogenolysis
V1b - anterior pituitaryACTH and -endorphin release
V2- renal collecting duct principal cells
free water reabsorption
Lee et al., Am Heart J 146:9-18, 2003
AVP regulation of water reabsorption from renal tubular AVP regulation of water reabsorption from renal tubular cellscells
AVPAVPAVP VAVP V22
ReceptorReceptor
AQP3AQP3
AQP4AQP4
Basolateral Basolateral membranemembrane
Luminal Luminal membranemembrane
HH22OO
HH22OOAQP2AQP2
Exocytic Exocytic InsertionInsertion
Endocytic Endocytic RetrievalRetrieval
cAMPcAMP
ATPATP
PKAPKA
RecyclingRecyclingvesiclevesicle
AQP2AQP2GTPGTP(Gs)(Gs)
Co
llectin
g d
uct
Co
llectin
g d
uct
Va
sa r
ect
aV
asa
re
cta CollectingCollecting Duct CellDuct Cell
Thyroid hormoneGlucocorticoid Dependent
Renal Concentrating MechanismRenal Concentrating Mechanism
Cortex
Medulla
NaH2O
Dilute
400
800
1100
H2O
H2O
Concentrated
10+ Liters/day
ADH PresentNa
H2O
300
Modified from Schrier, Renal and Electrolyte Disorders,
Na
Renal Diluting MechanismRenal Diluting Mechanism
Cortex
Medulla
NaH2O
Dilute
400
500
600
H2O
Na
Dilute
10+ Liters/day
ADH AbsentNa
H2O
Modified from Schrier, Renal and Electrolyte Disorders,
AVP Stimulation and EffectsAVP Stimulation and Effects
hyperosmolalityhyperosmolalityhypovolemia hypovolemia angiotensin IIangiotensin II
vasoconstrictionvasoconstriction renal Hrenal H22O O
reabsorptionreabsorption
baroreceptors baroreceptors natriuretic natriuretic peptidespeptides
AVPAVP
––++
V1a ReceptorsV1a Receptors V2 Receptors V2 Receptors
PainPainNauseaNausea
++
Adapted from Orlandi, 2009
ADH SecretionADH Secretion
290 300 310280270
ADHPlasmaLevels
ADH levels increase Markedly as soon as The plasma osmolalityincreases about 285
Plasma Osmolality
GoldilocksGoldilocksApproach to EndocrinologyApproach to Endocrinology
GoldilocksGoldilocksApproach to EndocrinologyApproach to Endocrinology
Too Hot
Too Cold
Just right
Hyperfunction
Hypofunction
Normal Function
Syndrome of Inappropriate ADH
DiabetesInsipidus
Diabetes InsipidusDiabetes Insipidus
ADH Deficiency
Diabetes InsipidusDiabetes Insipidus((ADH Deficiency)ADH Deficiency)
• Symptoms:– Polyuria (>2,000 cc/d)
• If pituitary, usually sudden onset
– Polydipsia• If pituitary, usually ice cold water
• Signs– Dehydration– Hypernatremia– Normokalemia– Inappropriately dilute urine
Diabetes InsipidusDiabetes Insipidus
• Differential Diagnosis– Osmotic diuresis (e.g. glucose)– Excessive fluid intake
• Psychogenic• Central• Secondary
– Nephrogenic Diabetes Insipidus– Central Diabetes Insipidus (ADH
deficiency)
Differential Diagnosis of Nephrogenic Differential Diagnosis of Nephrogenic Diabetes Insipidus (partial list):Diabetes Insipidus (partial list):
• Genetic• Chronic renal disease
– Polycyctic disease– Pylonephritis– Ureteral obstruction– Advanced renal failure
• Electrolyte disorders– Hypokalemia– Hypercalcemia
• Drugs– Alcohol– Lithium– Many others
• Miscellaneous– Multiple myeloma– Amyloidosis– Sjoger's disease– Sarcoidosis
Differential Diagnosis of Central Differential Diagnosis of Central Diabetes InsipidusDiabetes Insipidus
• Pituitary tumor– Functioning (Prolactin, Growth Hormone etc)– Non-functioning– Craniopharyngioma– Dysgerminoma– Metastatic tumor (breast, lung)
• Trauma– Surgery– Head trauma
• Inflammation– Infundibulo-hypophysitis– Granulomatous disease (histiocytosis X, Sarcoid,
Tuberculosis)• Genetic
Diabetes Insipidus: Clinical Diabetes Insipidus: Clinical EvaluationEvaluation
• Water deprivation test:– Complete fast– Measure hourly urine and serum electrolytes,
orthostatic blood pressure and weight– When plasma osmolarity ≥ 295 or urinary
osmolarity is stable, then give • DDAVP 5mcg. s.c.
– Interpretation:• Lack of ability to concentrate urine - DI• Good response to DDAVP - Central DI• No response to DDAVP – Nephrogenic DI
Central Diabetes InsipidusCentral Diabetes InsipidusTreatmentTreatment
• Desmopressin (1-desamino-8-D-arginie vasopressin)
– Commercial names: DDAVP, Minerin – Long-acting ADH analog
• Intra-nasal -- 10-40 mcg ever 8-12 hours
• Oral: 0.05 - 0.4 mg every 8-12 hours
• IV/SC: 1-2 mcg every 8-12 hours
– Monitor:• Electrolytes -- SIADH
Syndrome of Inappropriate ADHSyndrome of Inappropriate ADH
Syndrome of Inappropriate ADH Syndrome of Inappropriate ADH (SIADH)(SIADH)
• Clinical findings:– Hyponatremia– Normokalemia – Euvolemia (mild volume expansion)
SIADH - Water and Sodium BalanceSIADH - Water and Sodium Balance
• Increased ADH activity– Decreased free water clearance– Increased total body water
• Hyponatremia• Increased ECF volume
• Increased ECF volume– Increased GFR– Decrease proximal nephron Na+ reabsorption– Increased sodium loss– Minimizing increased ECF volume
• No edema– Worsening hyponatremia
Prevalence of dysnatremias at initial presentation to a health care provider
0.49
28.2
1.430.060.17
21
0.53 0.010.03
7.2
0.72 0.010
5
10
15
20
25
30
Na < 116 Na < 135 Na > 145 Na > 165
Prevalence (%)
Acute hospital careAmbulatory hospital careCommunity care
Hawkins. Clin Chim Acta 337:169-172, 2003
(data from 303,577 samples on 120,137 patients available for analysis)
Symptomatic hyponatremia: neurological manifestations
• headache
• irritability
• nausea/vomiting
• mental slowing
• confusion/delerium
• disorientation
• stupor/coma
• convulsions
• respiratory arrest
life-threatening, usually acute
symptomatic but less impaired; usually chronic
normal brain hyponatremic brain
Acute hyponatremia can cause death from cerebral edema and brain herniation
Neurological symptoms are correlated with the level of hyponatremia, but with considerable
individual variability across patients
Arieff et al., Medicine 55:121-129, 1976
Robertson et al. Robertson et al. Am J Med Am J Med 72:339-353, 198272:339-353, 1982
Plasma AVP levels are inappropriately elevated Plasma AVP levels are inappropriately elevated in most patients with SIADHin most patients with SIADH
0
7
1011
98
654321
230 240 250 260 270 280 290 300 310
Plasma Osmolality (mOsm/kg)
Pla
sma
Vas
op
ress
in (
pg
/mL
)
Normal Normal RangeRange
TumorsExtrathoracicMediastinalPulmonary
CNS DisordersAcute psychosisHemorrhageInflammatory and
demyelinating diseasesMass lesionsStrokeTrauma
DrugsCarbamazepine PhenothiazinesChlorpropamide Prostaglandin-synthesis Clofibrate inhibitorsCyclophosphamide SSRIs Desmopressin MAO inhibitorsNicotine Tricyclics Oxytocin VincristineOpiates
Pulmonary DisordersAcute respiratory failureInfectionsPositive-pressure ventilation
SIADH
Causes of SIADHCauses of SIADH
MiscellaneousHIV infectionIdiopathicPainPostoperative stateProlonged exerciseSenile atrophySevere nausea
Syndrome of Inappropriate ADH Syndrome of Inappropriate ADH (SIADH)(SIADH)
• Diagnosis:– Hyponatremia– Inappropriately elevated urine sodium– No volume depletion or severe volume expansion
• Etiology:– Glucocorticoid deficiency– Hypothyroidism– Pulmonary lesions– CNS lesions– Drugs (Chlorpropamide)
• Treatment:– Glucocorticoid/Thyroid hormone replacement (if
indicated)– Water deprevation– V2 receptor antagonists (in clinical trials)
Anterior Pituitary Gland AxesAnterior Pituitary Gland Axes
TSHThyroidGland
Adrenal Gland
ACTH
LHFSH
Testes/Ovaries
GH Prolactin
IGF-1
Distribution of Endocrine Cells in Distribution of Endocrine Cells in PituitaryPituitary
Posterior Pituitary
LHFSH10%
ACTH20%
TSH5%
GH50%
PRL15%
LHFSH10%PRL
15%
GH50%
ThyrotropinReleasing Hormone
CorticotropinReleasingHormone
GrowthHormoneReleasingHormone
Somatostatin(Somatotropin
Release Inhibiting
Factor)
Dopamine
GonadotropinReleasingHormone
Stimulator of secretion
Inhibitor of secretion
Pituitary Control of Thyroid/AdrenalPituitary Control of Thyroid/Adrenal
Corticotropin Releasing Hormone
Adreno-Cortico Trophic Hormone
Thyroid Stimulating Hormone
ThyrotropinReleasingHormone
Pituitary Gonadal Axis
Loss of Pituitary FunctionLoss of Pituitary Function
Loss of Pituitary FunctionLoss of Pituitary Function
• Functional abnormalities– Gonadotrophins -- Gonadal Insufficiency– ACTH -- Adrenal Insufficiency– Thyroid -- Hypothyroidism– GH – Growth hormone deficiency– Prolactin -- No syndrome– Anti-diuretic hormone -- Diabetes Insipidus
• Structural abnormalities– Visual field disturbance– Cranial nerve dysfunction– CNS leak
Loss of Pituitary Function: EtiologyLoss of Pituitary Function: Etiology
• Congenital• Pituitary tumors
– Functional– Non-functional
• Non-pituitary tumors– Craniopharyngioma– Metastases
• Trauma– Surgical– Head trauma
• Inflammation– Autoimmune
hypophysitis– Granulomatous disease
• Histiocytosis X• Sarcoid• Tuberculosis
– Rathke’s pouch rupture
Anterior Pituitary Function TestsAnterior Pituitary Function Tests(Stimulation tests)(Stimulation tests)
• Thyrotrophin Releasing Hormone (TRH)
• Gonadotrophin Releasing Hormone (GnRH)
• Metyropone stimulation test
• GH-specific tests– Clonidine, Arginine, Exercise, L-dopa
• Insulin-induced hypoglycemia (ITT, IST)
• Combined pituitary function test– ITT + TRH + GnRH
Hormone Replacement Therapy in Hormone Replacement Therapy in Panhypopituitary PatientPanhypopituitary Patient
• Adrenal Cortex:– Dexamethasone 0.25 - 0.75 mg/d– Prednisone 5-7.5 mg/d– Hydrocortisone 15-30 mg/d– Cortosone Acetate 25-37.5 mg/d
• Thyroid:– Levothyroxin 100-200 mcg/d
• Maintain T4 level in upper normal range
• Gonadal Steroids:– Estrogen/Progesterone or Testosterone
• Desmopressin• Growth Hormone
Hypopituitarism -- TreatmentHypopituitarism -- Treatment
• Treatment:– Hormonal Replacement– Surgical
• Most tumors require surgery– Radiation
• Small effect• High probability of pituitary dysfunction• Low probability of secondary tumor• May have long-term subtle neurologic effects
– Medical• Steroids for hypophysitis• Specific treatment for granulomatous disease• Rarely responsive to bromocriptine or octreotide
Growth Hormone
Growth Hormone (GH)Growth Hormone (GH)
• Gene:– Chromosome 17 q 22-24– 191 amino-acids
• Protein– Species specific– Binds to 2 specific plasma proteins
• Low affinity, high capacity -- significance not known• High affinity -- identical to extracellular domain of GH
receptor– Absent in GH-receptor deficient states (Laron Dwarf)– Decreased in GH excess– Biologic significance
» Decreased clearance?» Buffer effect?
• Receptor– Highly species specific
Diurnal Variation in Pulsatile Growth Diurnal Variation in Pulsatile Growth Hormone SecretionHormone Secretion
Regulation of GH SecretionRegulation of GH Secretion
SS
GRH
Acetylcholine
GH
IGF-1+
T3
Sleep
?Dopamine
GlucoseTRH
Arginine
InhibitionStimulation
Alpha adrenergicOpiatesGABA
Somatostatin
Growth HormoneReleasing Hormone
Insulin-like Growth Factor 1
Growth-Hormone: Growth-Hormone: Regulation of SecretionRegulation of Secretion
• Growth Hormone Releasing Hormone (GRH)– 40 AA peptide, structurally similar to Glucagon
and Secretin– Secreted in pulsitile manner– Interacts with somatostatin to create normal
pulsitile GH secretion pattern– Continuous stimulation with GRH results in
down-regulation of receptors, but pituitary still responsive
– GRH-stimulated GH secretion can be inhibited by Somatostatin
Growth-Hormone: Growth-Hormone: Regulation of SecretionRegulation of Secretion
• Somatostatin – 2 isoforms: 14 and 28 Amino Acids
synthesized from same pro-hormone molecule– Pulsitile secretion with biologic half-life 1-3
minutes– Suppresses both GH and TSH– Produced in hypothalamus, brain, pancreatic
islets, GI tract– At least 5 different receptor sub-types– In hypothalamus acts as neuropeptide, secreted
by hypothalamic neurons and carried to pituitary by portal system
Somatostatin - StructureSomatostatin - Structure
COOHNH2Prepro-somatostatin
Pro-somatostatin
Somatostatin - 28
Somatostatin -14
COOH
COOH
COOH
116
28
14
Somatostatin -Cellular ActionSomatostatin -Cellular Action
ACGi
Phospholipase C
Tyrosine phosphatase
Somatostatin 14
Somatostatin 28
Ca++
K+
close
5 ReceptorSubtypes
12
34
5
ATP
cAMP
GH Receptor DimerizationGH Receptor Dimerization
Activation
Binding site 1Binding site 2
JAK Kinase
Signal Transduction andTranscription Activator
Insulin-Like Growth Factor 1Insulin-Like Growth Factor 1
• 70 Amino Acids, structurally similar to Pro-insulin
• GH stimulates secretion. • Blood levels decreased by starvation and liver
disease• Most GH-sensitive tissues produce IGF-1 which
acts in a paracrine fashion.• Circulating IGF-1 primarily of hepatic origin • Circulating IGF-1 is bound to at least 6 different
IGF binding proteins.– IGFBP-3 is regulated by GH
Growth Hormone ActionsGrowth Hormone Actions
• Growth promoting, Insulin-like– Increased:
• Protein synthesis• Amino acid
transport• Muscle mass• Bone and cartilage
growth• Cell proliferation
• Anti-Insulin– Lipolysis
– Ketogenesis
– Hyperglycemia
– Peripheral insulin resistance
Growth-Hormone Deficiency (1)Growth-Hormone Deficiency (1)
• Children– Increased insulin sensitivity
• Hypoglycemia (mostly infants and small children)
– Decreased linear growth (Dwarfism)– Decreased muscle mass, increased fat mass
• Adults– Decreased muscle mass, increased fat mass– Decreased sense of well being
Growth-Hormone Deficiency (2)Growth-Hormone Deficiency (2)
• Etiology:– Children:
• Genetic: – Isolated GH deficiency– Growth hormone mutations– GH receptor deficiency (Laron Dwarf)– Multiple pituitary hormone deficiency (PIT-1, PROP-1)
• Tumor:– Craniopharyngioma– Dysgerminoma
– Adult:• Trauma / Surgery / Radiation• Tumor:
– Functioning or non-functioning pituitary– Craniopharyngioma– Metastatic (breast)
Growth-Hormone Deficiency (3)Growth-Hormone Deficiency (3)
• Diagnosis– Stimulation tests:
• Clonidine
• L-dopa
• Arginine
• Exercise
• Insulin-induced hypoglycemia
– Under most circumstances, at least 2 abnormal tests required for definitive diagnosis
GH Stimulation TestsGH Stimulation Tests
InhibitionStimulation
SS
GRH
GH
IGF-1+
Dopamine
Acetylcholine
Sleep Arginine
Alpha adrenergic
(Clonidine)Stress (Exercise, ITT)
Growth-Hormone Deficiency (4)Growth-Hormone Deficiency (4)
• Treatment– Human growth hormone replacement
• Human pituitary origin– Expensive and insufficient supplies– Creutzfeld-Jacob disease
• Recombinant DNA technology– Plentiful– Safe– Expensive
– Use in GH-deficient adults standard in most countries
– Use in elderly is controversial and not accepted by most.
Growth-Hormone ExcessGrowth-Hormone Excess
• Childhood– Gigantism
• Adults– Acromegaly
• Etiology– 98%: GH-producing pituitary tumor– 2%: Ectopic GHRH secretion
• Small cell lung cancer• Bronchial or intestinal carcinoid tumors• Pancreatic islet cell tumor• Pheochromocytoma
GigantismGigantism
28 October 2013, Turkey
Duomo Di Milano
Growth-Hormone ExcessGrowth-Hormone Excess
• Childhood– Gigantism
• Adults– Acromegaly
• Etiology– 98%: GH-producing pituitary tumor– 2%: Ectopic GHRH secretion
• Small cell lung cancer• Bronchial or intestinal carcinoid tumors• Pancreatic islet cell tumor• Pheochromocytoma
Acromegaly (1)Acromegaly (1)
• Prevalence: 40-50 / 106
• Incidence: 3-4 / 106
• Mean age of onset: 32 years
• Mean age at diagnosis: 42 years
• Prognosis: 2x increased mortality
Acromegaly - Signs and SymptomsAcromegaly - Signs and Symptoms
• GH Excess– Enlargement of hands and
feet– Thick skin– Skin tags– Sweating– Sleep Apnea– Carpal Tunnel Syndrome– Glucose intolerance– Osteoarthritis– Colonic Polyps
• Tumor-related– Headache
– Visual field defect
– Loss of pituitary function
• Gonadotrophins
• TRH - hypothyroid
• ACTH - Addison’s
Acromegaly (3):Acromegaly (3):DiagnosisDiagnosis
• Abnormal net GH secretion over time:– 24 hour GH profile (Night-time GH levels)– Elevated IGF-1– Elevated IGFBP-3
• Non-suppressible GH secretion– Glucose suppression
• OGTT
• High-carbohydrate meal
Regulation of GH SecretionRegulation of GH Secretion
SS
GRH
GH
IGF-1+
TRH
InhibitionStimulation
Glucose
Dopamine
Acromegaly Treatment OptionsAcromegaly Treatment Options
• Surgery
• Radiation
• Medical
Natural SomatostatinNatural Somatostatin
• Clinical utility is limited by:– Plasma half- life 1-3 minutes
• Drug delivery:– Intravenous only– Specificity poor
• Cessation of treatment associated with rebound phenomenon
Synthetic Somatostatin Synthetic Somatostatin Analogue OctreotideAnalogue Octreotide
• Clinical utility is enhanced due to:– Plasma half- life 1-2 hours– Drug action Variable 3-12h– Drug delivery IV or SC
• Specificity:– Partial selectivity
• (GH>glucagon>gastric acid>insulin)
• No rebound phenomenon upon cessation of treatment
Somatostatin AnalogsSomatostatin Analogs
Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys
Native Somatostatin-14S - S
dPhe-Cys-Phe-dTrp-Lys-Thr-Cys-Thr(ol)Octreotide: S - S
dPhe-Cys-Phe-dTrp-Lys-Thr-Cys-Thr(ol)Octreoscan: 111In-DTPA S - S
Lanreotide: dnal-Cys-Tyr-dTrp-Lys-Val-Cys-Thr
S - S
SomatostatinSomatostatinActions on the Gastro-intestinal TrackActions on the Gastro-intestinal Track
Lamberts et al NEJM, 1996
Adverse Side-Effects of Adverse Side-Effects of Somatostatin AnalogsSomatostatin Analogs
• Common side-effects– Pain at injection site– Abdominal pain and
cramps– Diarrhea, steatorrhea– Impaired glucose tolerance– Gallstone formation
Decrease side-effects by:Avoid fat intake for first 2 weeks after initiation of therapyShort acting preparations:
Warm injection to room temperature before administrationInject slowlyUse highest possible concentration of drugInject about 1 hour after meals
• Rare side-effects– Rash– Alopecia – Water intoxication– Hypoglycemia
Acromegaly: Novel Treatment Acromegaly: Novel Treatment Approaches Approaches
• Growth hormone antagonists– Growth hormone analog with one binding site
mutated
Dominant Negative GH AnalogDominant Negative GH Analog
Binding site 1 Binding site 2
Binding site 2 Mutated
No dimerizationNoactivationNo signal transduction
Acromegaly: Novel Treatment Acromegaly: Novel Treatment Approaches Approaches
• Growth hormone antagonists– Growth hormone analog with one binding site
mutated– Dominant negative activity– Disadvantages:
• GH levels not suppressed
• Difficult to monitor
• Effect on tumor unknown– May actually stimulate tumor growth
ProlactinProlactin
ProlactinProlactin
• 198 Amino acid peptide structurally related to Growth Hormone (GH)
• Lactotrophs which make up 40-50% of the endocrine cells of the anterior pituitary
• During fetal development, prolactin cells appear to differentiate from GH cells.
• Some cells maintain the ability to produce both GH and Prolactin.
• Glycosylated and non-glycosylated forms have different bioactivities.
Cellular Action of ProlactinCellular Action of Prolactin
• Membrane bound receptor• Action appears not to be cAMP
dependent• Action may be mediated through
membrane phospholipase activity resulting in protein kinase C activation and calcium influx
Effects of HyperprolactinemiaEffects of Hyperprolactinemia
• Hypothalamus:– Inhibition of GnRH production
• Mammary gland:– Direct - stimulation of milk production and
secretion – Indirect - decreased estrogen effect
• Ovaries:– Direct - decreased responsiveness to
gonadotrophins – Indirect - decreased gonadotrophin secretion at
level of hypothalamus/pituitary
Effects of HyperprolactinemiaEffects of Hyperprolactinemia
• Testes:– Direct - decreased responsiveness to
gonadotrophins – Indirect - decreased gonadotrophin secretion at
level of hypothalamus/pituitary
• Bones:– Indirect - due to gonadal steroid deficiency
Prolactin - Diurnal VariationProlactin - Diurnal Variation
SW
I+II
WAKE
REM
200
400
600
24 Hour Clock Time
08 14 20 02 08
Sleep
Pla
sma
Pro
lact
in (
pm
ol/
l)
Control of Prolactin SecretionControl of Prolactin Secretion
Lactotropes
Estrogen
Thyroid Hormone
Prolactin
+Hypothalamus
+
-
-
Breast milk synthesis
-
PRFs(TRH)Dopamine
(Other PIFs?)
Prolactin Effect on Prolactin Effect on Gonadotrophin SecretionGonadotrophin Secretion
GnRH
+
Inhibits
Hyperprolactinemia
Stimulates
LH
Gonadotrophs
Gonads
Hypothalamus
Pituitary
Dopamine
Differential Diagnosis of Differential Diagnosis of HyperprolactinemiaHyperprolactinemia
• Prolactin producing pituitary tumor– Microprolactinoma (<1 cm)– Macroprolactinoma (>1 cm) – Mixed tumors (30% of GH producing tumors)
• Chronic renal failure– Decreased clearance and suppressibility
• Thoracic sensory nerve stimulation– Chest wall burns, incisions, trauma etc.
• Mental and physical stress– May be mediated through ß-endorphin
suppression of dopamine secretion
Differential Diagnosis of Differential Diagnosis of HyperprolactinemiaHyperprolactinemia
• Medications– Alpha-methyldopa, reserpine– Phenothiazines, butyrophenones, – benzamides (metoclopramide, sulpride) Estrogens
– H2-receptor blockers (cimetidine)– Opiates
• Hypothyroidism• Decreased dopamine delivery to pituitary
– Pituitary, suprasellar and hypothalamic lesions– Radiation damage to the hypothalamus
Differential Diagnosis of Differential Diagnosis of HyperprolactinemiaHyperprolactinemia
• Prolactin levels > 6,500 mIU/l is usually indicative of macroprolactinoma.
• Stalk compression, medications, hypothyroidism and stress usually result in prolactin levels < 1,500 and virtually always less than 5,000 mIU/l.
• Microprolactinomas, mass lesions compressing the pituitary stalk frequently present with similar prolactin levels.
Prolactinoma: Results of TreatmentProlactinoma: Results of Treatment
Response Recurrence
SurgeryMicroprolactinoma 60-80% 50%
Macroprolactinoma 10-30% ~100%
Radiotherapy Normalization of PRL after ~10 years
Medical TherapyMicroprolactinoma >90%Macroprolactinoma 50-80%
The EndThe EndThe EndoThe Endo
Schematic View of an ADH-Sensitive Collecting Schematic View of an ADH-Sensitive Collecting Tubule CellTubule Cell
ATP
cAMP
A
ADH binds to the contraluminal surface, activating adenylyl cyclase and generating cAMP. This causes cytoplasmic tubules containing water channels, aquaporins (A), to fuse with the luminal membrane (B), allowing free transport of water into the cell. C = particle aggregates in luminal
membrane.
kinase
B
C H2OH2O Cortisol and
Thyroid Hormone requiring
ADH receptor
Adenyl cyclase
cAMP
ATP
Control of ADH SecretionControl of ADH Secretion
Osmoreceptor(preoptic nucleusanterior hypothalamus)
Paraventricular nucl.Supraoptic nucl.
PosteriorPituitary
Nausea
Pain
Baroreceptrors Aorta Carotids Atria Thoracic veinsDepolarization
ADH+Neurophysin(1.5 hours)
Water
NaGlucose
Acromegaly: Treatment optionsAcromegaly: Treatment options
Transsphenoidal Surg. Radiotherapy Octreotide Bromocriptine
Micro Macro
GH <5 mcg/l 80% 50-60% 77% (15 years) 65% 20%
GH <2 mcg/l 70% 40% no data 40% no data
Nl IGF-1 50% 50% no data 50% 10%
Disadvantages
Recurrence 5-10%* Late response inconv. & cost Low efficacy
Complications
Hypopit. 15% >50% None None
Other DI- 2-3% Neuro deficits Gallstones Nausea, hypotens.
* Actual long-term recurrence probably higher
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